Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy

A tetravalent dengue vaccine (CYD-TDV) protective against severe virologically confirmed dengue (VCD) and decreases incidence of hospitalization because of VCD for 5 years in patients with previous dengue exposure before vaccination, according to a case-cohort study in The New England Journal of Medicine that reanalyzed data from vaccine efficacy studies.

Excess hospitalizations for dengue were observed among vaccine recipients 2 to 5 years of age in the original efficacy trials (Clincaltrial.gov: NCT00842530, NCT01983553, NCT01373281, and NCT01374516) and precise risk estimates according to observed dengue serostatus could not be determined because of limited baseline sample collections. Investigators here developed a dengue anti–non-structural protein 1 (NS1) IgG enzyme-linked immunosorbent assay and using samples from month 13 inferred serostatus for post hoc safety and efficacy analyses.

The cumulative 5-year incidence of hospitalization for VCD among dengue-seronegative patients 2 to 16 years of age was 3.06% for patients receiving the vaccine and 1.87% among control participants, with a hazard ratio (vaccine vs control) through data cutoff of 1.75 (95% CI, 1.14-2.70). Among seronegative participants aged 9 to 16 the cumulative incidence of hospitalization was 1.57 among vaccine recipients and 1.09% for controls, hazard ratio of 1.41 (95% CI, 0.74-2.68). Similar trends were also found for severe VCD. Among seropositive patients 2 to 16 years of age and patients 9 to 16 years of age, the cumulative incidence of hospitalization for VCD was 0.75% and 0.38%, respectively, among vaccine recipients, and 2.47% and 1.88% among control participants, with hazard ratios of 0.32 (95% CI, 0.23-0.45) and 0.21 (95% CI, 0.14-0.31). The risk of severe VCD was also lower among seropositive vaccine recipients than seropositive controls.

The results support the hypothesis that without previous dengue exposure, the vaccine can mimic a primary infection and increase the risk of severe dengue during subsequent infections. The results were supported by a general consistency of findings obtained from multiple analytic methods, though each relied on its own assumptions. The authors also note that “although we used a new assay after characterization and qualification, neither the anti-NS1 assay nor the PRNT is validated or registered for the purpose of determining baseline dengue serostatus.” It is therefore reasonable to expect that predictive values will vary according to epidemiological contexts. Still, the results may affect implementation of dengue vaccine programs and highlight the need for a rapid, reliable test for previous dengue exposure.

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Sridhar S, Luedtke A, Langevin E, et al. Effect of dengue serostatus on dengue vaccine safety and efficacy [published online June 13, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1800820